Discovery of a potent inhibitor of anaplastic lymphoma kinase with in vivo antitumor activity.
Basic Information
ID: ALA2040771
Journal: ACS Med Chem Lett
Title: Discovery of a potent inhibitor of anaplastic lymphoma kinase with in vivo antitumor activity.
Authors: Ott GR, Tripathy R, Cheng M, McHugh R, Anzalone AV, Underiner TL, Curry MA, Quail MR, Lu L, Wan W, Angeles TS, Albom MS, Aimone LD, Ator MA, Ruggeri BA, Dorsey BD.
Abstract: A series of novel 7-amino-1,3,4,5-tetrahydrobenzo[b]azepin-2-one derivatives within the diaminopyrimidine class of kinase inhibitors were identified that target anaplastic lymphoma kinase (ALK). These inhibitors are potent against ALK in an isolated enzyme assay and inhibit autophosphorylation of the oncogenic fusion protein NPM-ALK in anaplastic large cell lymphoma (ALCL) cell lines. The lead inhibitor 15, which incorporates a bicyclo[2.2.1]hept-5-ene ring system in place of an aryl moiety, activates the pro-apoptotic caspases (3 and 7) and displays selective cytotoxicity against ALK-positive ALCL cells. Furthermore, 15 provides more than 40-fold selectivity against the structurally related insulin receptor, is orally bioavailable in multiple species, and displays in vivo antitumor efficacy when dosed orally in ALK-positive ALCL tumor xenografts in Scid mice.
CiteXplore: 24900237
DOI: 10.1021/ml100158s
Patent ID: ┄